Newly Recognized Dementia, LATE May Impact 40 Percent of Older Persons

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Toxic clumps of two proteins, beta-amyloid and tau, are the well-known hallmarks of Alzheimer’s disease, the most common cause of dementia. TDP-43, another protein that has been deemed a bad actor on this list, is becoming more prominent in recent years. It contributes to a form of cognitive impairment that is surprisingly common among older people and has even received its own designation as a separate condition from other dementias such as Alzheimer’s. TDP-43, like tau and amyloid, can form into clumps in the brain that cause cognitive impairment. This condition is known as limbic predominant age-related TDP43 encephalopathy (or LATE). A recent study has found that LATE may be both highly prevalent in the older general population and in individuals with Alzheimer’s disease, leading to worsening cognition in the latter group.

“LATE is not only an important, separate cause of Alzheimer’s-type dementia,” says Julie Schneider, a neurologist and neuropathologist at Rush University in Chicago. “It seems to also be important within a large subset of people with Alzheimer’s disease pathology.”

TDP-43 first became known in 2006 by researchers. Discovered contorted VersionsThe protein was found in brains of patients suffering from amyotrophic lateral sclerosis and frontotemporal lobar dementia (FTLD). One year later, scientists reported that Also, pathological TDP-43-43 was present in the brains of people with Alzheimer’s disease and hippocampal sclerosis, a disease associated with pathological changes in the hippocampus. In this latter group, TDP-43 aggregates typically appeared in the limbic regions, such as the hippocampus and amygdala, areas also affected by Alzheimer’s disease.

Once the scientific community became aware of TDP-43, “people from all over the world were seeing manifestations of it,” says Peter Nelson, a neuropathologist at the University of Kentucky. There was at that time no common term for the condition. In 2018, researchers convened in Atlanta to discuss TDP-43 brain pathology. In 2019, a consensus paper was published from the results of that meeting. LATE was the first term to be introduced.Many considered this a rare brain disorder. At the time, the “LATE” label had its critics, however—and there are still some in the research community who question whether the moniker is necessary.

Nelson, an author of the consensus paper, says that LATE provided a description for a third of cases where previously there was no standardized diagnosis—and helped catalyze new research in the field. “One of the very satisfying things about that 2019 paper is that it coincided with a great leap in the number of people studying this,” he adds. “It turns out that this disease is way more common than people think—and it’s way more impactful than is frequently appreciated.”

A Common Condition

Studies to date suggest that LATE—as the name implies—tends to occur later in life, in people who are in their 80s or older.

Clinically, LATE looks very much like Alzheimer’s, Nelson says. While memory loss is the most obvious sign of the disorder, it can also be a precursor to other cognitive impairments. Nelson adds that, symptom-wise, “pure” LATE tends to be associated with more gradual decline than “pure“ Alzheimer’s—but that the combination of Alzheimer’s and LATE appears to lead to more swift and severe symptoms than either alone.

This is the most recent study published in Acta Neuropathologica last month. It was done by Schneider, Nelson, and their colleagues from various research institutions. We analyzed data from more than 6000 deceased people(62% of women) who donated their brains for research. These participants died at the average age 88 years old and belonged 13 community groups in the U.S.A, U.K, Brazil, Austria, Finland, and Brazil. 42% of the participants had dementia. 15% had mild cognitive impairment and 33% were cognitively normal.

The research team examined brain tissue and cognitive characteristics, including the status of the participants before death. They found that around 40% of them had LATE-related pathological changes. Among participants with amyloid plaques—a telltale sign of Alzheimer’s disease—in their brain, the proportion of LATE was approximately 50 percent. “This paper really helped solidify the idea that LATE is much more common than we might have previously thought,” says Nina Silverberg, director of the Alzheimer’s Disease Centers Program at the National Institute on Aging, who was not involved in the study. Silverberg organized the 2018 workshop that culminated in the naming of LATE.

The researchers also found evidence that, among participants with Alzheimer’s, those who also had LATE tended to exhibit greater cognitive impairments than those who did not have LATE. Schneider doesn’t know why this is so. One explanation could be that damage to multiple pathological processes may just lead to more damage. She adds that it is unclear if they are able to feed on one another, making things worse.

Currently, a definitive LATE diagnosis can only be made during an autopsy, unlike Alzheimer’s, where the pathological hallmarks such as amyloid plaques can be identified by imaging the brain with positron-emission tomography or by assessing the cerebrospinal fluid, the liquid surrounding the brain and spinal cord.

The search for a biomarker that detects TDP-43 is currently underway—but in the meantime, clinicians are nearing development of a means to diagnose this disease while patients are still alive, according to Schneider. Because biomarkers for Alzheimer’s are available, if a patient comes to the clinic with a pattern of memory loss indicative of Alzheimer’s and appear to have a shrunken hippocampus—but without any signs of amyloid—it may be a telling sign. “I put my bets on the person having LATE,” Schneider says. “And I think a lot of the other clinicians are surmising the same thing now.”

What is a New Condition?

Not everyone accepted LATE when it was first introduced to scientists. In response to the consensus paper, a group of researchers—including some that were involved in the initial discovery of TDP-43—wrote an An opinion piece that was questionedWhether the new term was necessary. “The term LATE is proposed as a catchy acronym to describe the presence of TDP-immunoreactive lesions in Alzheimer’s disease, as well as in older adults,” the authors wrote. “However, we question the term’s novelty and nosology, the framework that seemingly separates LATE from FTLD-TDP and other diseases.”

William Hu, a Rutgers University neurologist and one of the authors, continues to question whether LATE should be considered a separate disorder. In Hu’s view, TDP-43 aggregates are a pathological feature of the various diseases in which they have been found—and they should not be lumped together as a single entity. Hu states that LATE should be treated as a confirmed entity before any other diagnostics can be applied.

Hu states that TDP43 pathology is the main cause of ALS/FTLD. But when it comes to Alzheimer’s, there are still important questions about TDP-43 that need to be tackled. Is the TDP-43 accumulation a side effect or contributing to pathology? Is TDP-43 related to amyloid buildup or an independent process?

The controversy around the LATE label has helped raise important questions—and sparked efforts to address them, Silverberg says. Many unknowns about LATE remain, and better understanding of this condition may not only help find therapeutics for individuals with TDP-43 pathology but also pave the way to better clinical trials for Alzheimer’s disease.

“Maybe part of the reason we have had so many failed trials is that some people who looked like they had Alzheimer’s disease—before we had biomarkers we could use during life—may have had something else,” Silverberg says. “At least with the new trials, we’ll know that the target is amyloid. They are including amyloid—and hopefully, in the future, we’ll be able to do the same with TDP-43.”

Ultimately, Schneider says, “I think what’s not important so much as the name is the message. I think the motivation for all of us is to get out the word of how important it is to study LATE and TDP-43.”

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